The mechanisms underlying type-2 diabetic neuropathic pain (DNP) are unclear. This study investigates the coupling of postsynaptic density-95 (PSD-95) to N-methyl-D-aspartate receptor subunit 2B (GluN2B), and the subsequent phosphorylation of GluN2B (Tyr1472-GluN2B) in the spinal cord in a rat model of type-2 DNP. Expression levels of PSD-95, Tyr1472-GluN2B, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and its phosphorylated counterpart (Thr286-CaMKII), and α-amino-3-hydroxy-5-methyl-4-soxazole propionic acid receptor subtype 1 (GluR1) and its phosphorylated counterpart (Ser831-GluR1) were significantly increased versus controls in the spinal cord of type-2 DNP rats whereas the expression of total spinal GluN2B did not change. The intrathecal injection of Ro25-6981 (a specific antagonist of GluN2B) or Tat-NR2B9c (a mimetic peptide disrupting the interaction between PSD-95 and GluN2B) induced an antihyperalgesic effect and blocked the increased expression of Tyr1472-GluN2B, CaMKII, GluR1, Thr286-CaMKII, and Ser831-GluR1 in the spinal cords; the increase in spinal cord PSD-95 was not affected. These findings indicate that the PSD-95-GluN2B interaction may increase phosphorylation of GluN2B, and subsequently induce the expression of phosphorylation of CaMKII and GluR1 in the spinal cord of type-2 DNP rats. Targeting the interaction of PSD-95 with GluN2B may provide a new therapeutic strategy for type-2 DNP.

中文翻译：

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通过PSD-95-GluN2B耦合依赖性的GluN2B在脊髓中的2型糖尿病性神经性疼痛大鼠模型中，CaMKII和GluR1的激活。

2型糖尿病性神经性疼痛（DNP）的潜在机制尚不清楚。这项研究调查了突触后密度95（PSD-95）与N-甲基-D-天冬氨酸受体亚基2B（GluN2B）的偶联，以及随后在大鼠模型中脊髓中GluN2B（Tyr1472-GluN2B）的磷酸化。 2型DNP。PSD-95，Tyr1472-GluN2B，Ca ^2+的表达水平/钙调蛋白依赖性蛋白激酶II（CaMKII）及其磷酸化对应物（Thr286-CaMKII），以及α-氨基-3-羟基-5-甲基-4-甲基恶唑丙酸受体亚型1（GluR1）及其磷酸化对应物（Ser831 -GluR1）在2型DNP大鼠的脊髓中比对照组显着增加，而总脊髓GluN2B的表达未改变。鞘内注射Ro25-6981（GluN2B的特异性拮抗剂）或Tat-NR2B9c（破坏PSD-95和GluN2B的模拟肽）诱导了抗痛觉过敏作用，并阻止了Tyr1472-GluN2B，CaMKII，GluR1，脊髓中的Thr286-CaMKII和Ser831-GluR1；脊髓PSD-95的增加不受影响。这些发现表明PSD-95-GluN2B相互作用可能会增加GluN2B的磷酸化，然后诱导2型DNP大鼠脊髓中CaMKII和GluR1的磷酸化表达。靶向PSD-95与GluN2B的相互作用可能为2型DNP提供新的治疗策略。